Robert S. Rahimi

Complications of cirrhosis.

Purpose of review Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the past 18 months are reviewed. Recent findings Percutaneous liver biopsy can be safely performed in patients with advanced liver disease with minimal complications. Predictors of response to lactulose, probiotics and L-ornithine-L-aspartate therapy in minimal hepatic encephalopathy have been reported. Rifaximin was found to lead to better maintenance of remission and decreased re-admission rates in patients with cirrhosis and hepatic encephalopathy, and may improve driving performance in those with minimal hepatic encephalopathy. In a controversial study, patients with refractory ascites taking propranolol were found to have poorer outcomes, perhaps related to beta-blockade associated paracentesis-induced circulatory dysfunction. Terlipressin and albumin therapy currently appears to be the best medical therapy available in patients with type 1 HRS, although pentoxifylline may be effective to treat HRS in patients with cirrhosis and ascites. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared to nonselective beta-blockers. In patients with esophageal varices without bleeding, prophylaxis with variceal ligation or beta-blockers was similar in terms of bleeding, mortality, and adverse events. Erythromycin given 30 min prior to endoscopic evaluation in suspected EVH was associated with an overall benefit in visibility, duration of the procedure and length of hospital stay. Summary Refinement in clinical management strategies for patients with cirrhosis and its complications appears to continue to contribute to improved patient outcomes.

Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy The HELP Randomized Clinical Trial

IMPORTANCE Hepatic encephalopathy (HE) is a common cause of hospitalization in patients with cirrhosis. Pharmacologic treatment for acute (overt) HE has remained the same for decades. OBJECTIVE To compare polyethylene glycol 3350-electrolyte solution (PEG) and lactulose treatments in patients with cirrhosis admitted to the hospital for HE. We hypothesized that rapid catharsis of the gut using PEG may resolve HE more effectively than lactulose. DESIGN, SETTING, AND PARTICIPANTS The HELP (Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution) study is a randomized clinical trial in an academic tertiary hospital of 50 patients with cirrhosis (of 186 screened) admitted for HE. INTERVENTIONS Participants were block randomized to receive treatment with PEG, 4-L dose (n = 25), or standard-of-care lactulose (n = 25) during hospitalization. MAIN OUTCOMES AND MEASURES The primary end point was an improvement of 1 or more in HE grade at 24 hours, determined using the hepatic encephalopathy scoring algorithm (HESA), ranging from 0 (normal clinical and neuropsychological assessments) to 4 (coma). Secondary outcomes included time to HE resolution and overall length of stay. RESULTS A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in HESA score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P < .01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related. CONCLUSIONS AND RELEVANCE PEG led to more rapid HE resolution than standard therapy, suggesting that PEG may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute HE. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01283152.

Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is expected to rise along with the global obesity epidemic. As NAFLD is the most common cause of chronic liver disease in the United States, it has become a major health concern. It affects all ethnicities, with the highest prevalence among the Hispanic population. Individuals with nonalcoholic steatohepatitis (NASH), the more serious form of NAFLD, are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Since NAFLD is intricately associated with the metabolic syndrome and insulin resistance, increased risk of cardiovascular disease and mortality become a real concern. It has recently been shown that current nutrition trends, such as increased consumption of high-fructose corn syrup and certain types of fats, may have an important role in the increased NAFLD prevalence. As there are no ideal treatment options available for NAFLD, a multifaceted treatment approach should be tailored to each individual patient.

An Automated Model Using Electronic Medical Record Data Identifies Patients With Cirrhosis at High Risk for Readmission

BACKGROUND & AIMS Patients with cirrhosis have 1-month rates of readmission as high as 35%. Early identification of high-risk patients could permit interventions to reduce readmission. The aim of our study was to construct an automated 30-day readmission risk model for cirrhotic patients using electronic medical record (EMR) data available early during hospitalization. METHODS We identified patients with cirrhosis admitted to a large safety-net hospital from January 2008 through December 2009. A multiple logistic regression model for 30-day rehospitalization was developed using medical and socioeconomic factors available within 48 hours of admission and tested on a validation cohort. Discrimination was assessed using receiver operator characteristic curve analysis. RESULTS We identified 836 cirrhotic patients with 1291 unique admission encounters. Rehospitalization occurred within 30 days for 27% of patients. Significant predictors of 30-day readmission included the number of address changes in the prior year (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.05-1.21), number of admissions in the prior year (OR, 1.14; 95% CI, 1.05-1.24), Medicaid insurance (OR, 1.53; 95% CI, 1.10-2.13), thrombocytopenia (OR, 0.50; 95% CI, 0.35-0.72), low level of alanine aminotransferase (OR, 2.56; 95% CI, 1.09-6.00), anemia (OR, 1.63; 95% CI, 1.17-2.27), hyponatremia (OR, 1.78; 95% CI, 1.14-2.80), and Model for End-stage Liver Disease score (OR, 1.04; 95% CI, 1.01-1.06). The risk model predicted 30-day readmission, with c-statistics of 0.68 (95% CI, 0.64-0.72) and 0.66 (95% CI, 0.59-0.73) in the derivation and validation cohorts, respectively. CONCLUSIONS Clinical and social factors available early during admission and extractable from an EMR predicted 30-day readmission in cirrhotic patients with moderate accuracy. Decision support tools that use EMR-automated data are useful for risk stratification of patients with cirrhosis early during hospitalization.

Complications and outcomes in chronic liver disease.

Purpose of review Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS) and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the last 18 months are reviewed. Recent findings Predictors of response to lactulose therapy in hepatic encephalopathy have been reported, along with the effect of minimal hepatic encephalopathy on driving. Rifaximin was found to lead to better maintenance of remission and decreased readmission rates in patients with cirrhosis and hepatic encephalopathy. Satavaptan (a vasopressin receptor antagonist) was investigated for treatment of refractory ascites and appeared to be effective, but this compound is not currently approved by the US Food and Drug Administration (FDA). Patients with refractory ascites taking propranolol were found to have poorer outcomes than those not taking propranolol. Terlipressin currently appears to be the best medical therapy available for patients with type 1 HRS; the addition with albumin to terlipressin appeared to decrease mortality in patients with type 1 HRS. In primary prophylaxis of EVH, carvedilol was found to reduce the rate of initial bleeding compared with band ligation. Early transjugular intrahepatic portosystemic shunts placed in highly selected patients with acute EVH and a high risk of endoscopic failure decreased long-term mortality. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared with nonselective beta-blockers. Summary Refinement in clinical management strategies for patients with cirrhosis and its complications appear to continue to contribute to improved patient outcomes.

End-stage liver disease complications.

Purpose of review Chronic liver disease causes significant morbidity and mortality because of any number of complications including hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage (EVH). Recent findings Predictors of response to lactulose, probiotics, and L-ornithine-L-aspartate therapy in minimal hepatic encephalopathy (MHE) have been reported. Although rifaximin was slightly more effective than lactulose in the maintenance of remission and decreased re-admission in patients with MHE, it was not as cost-effective as lactulose. Beta-blockade has been associated with paracentesis-induced circulatory dysfunction. Those who respond to nonselective beta-blockers have a predictable overall lower probability of developing ascites and HRS. Noradrenaline was as effective as terlipressin for the treatment of type 1 HRS and was less costly. Hemorrhagic ascites, defined as an ascitic fluid red blood cell (RBC) count of at least 10 000/&mgr;l, appeared to be a marker for poor outcome in patients with cirrhosis. In patients with acute EVH, band ligation, pharmacologic vasoconstrictors, and antibiotics are effective; notably, intravenous proton pump inhibitor therapy in lieu of vasoconstrictors achieved similar hemostatic effects with fewer side-effects. Summary Refinement in the clinical management strategies for patients with cirrhosis and its complications appear to continue to contribute to improved patient outcomes.

Altered Mental Status in Cirrhosis: Etiologies and Outcomes

Background Cirrhotic patients admitted with altered mental status (AMS) represent a clinical challenge, as many potentially life-threatening diseases must be considered. Although many patients with AMS have hepatic encephalopathy (HE), other causes of AMS occur, and we hypothesized that these may have different outcomes. Aim We aimed to understand the causes of AMS in cirrhotic patients admitted to the hospital and investigate their associated outcomes. Methods We performed a retrospective cohort study in 1218 inpatients with cirrhosis. Altered mental status was defined a priori (HE, sepsis/infectious, metabolic, exogenous drugs/toxins, structural lesions, or psychiatric abnormalities). Results Patients with AMS had higher levels of serum bilirubin, international normalized ratio, blood urea nitrogen, creatinine, and lower levels of albumin and platelets than those with normal mental status (NMS) (P = < 0.001). The most common cause of AMS was HE, accounting for nearly half of all patients. Other causes of AMS included the following: sepsis/infection (23%), metabolic disorders (8%), drugs/toxins (7%), structural lesions (5%), psychiatric disorders (1%), or multiple causes (8%). Mortality in patients with AMS was 35% compared to 16% in those with NMS (P < 0.0001). Patients with sepsis/infection, structural lesions, or multiple disorders causing AMS had the highest mortality (61%, 68%, and 79%, respectively). Conclusions Nearly one third of admissions in cirrhotic patients were due to AMS, most commonly caused by HE. The overall mortality of patients admitted with AMS was greater than with NMS, particularly for those with infection or structural lesions, emphasizing the importance of a search for these causes of AMS in all patients with cirrhosis.

Hepatic Encephalopathy: Pharmacological Therapies Targeting Ammonia.

Hepatic encephalopathy (HE) is a major complication in patients with decompensated cirrhosis, leading to higher readmission rates causing a profound burden of disease and considerable health care costs. Because ammonia is thought to play a crucial role in the pathogenesis of HE, therapies directed at reducing ammonia levels are now being aggressively developed. Ammonia scavengers such as AST-120 (spherical carbon adsorbent), glycerol phenylbutyrate, sodium phenylacetate or sodium benzoate, and ornithine phenylacetate have been used to improve HE symptoms. A new approach, bowel cleansing with polyethylene glycol 3350, appears to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt HE (at 24 hours after treatment) than lactulose. Extracorporeal devices, although now used primarily in research settings, have also been utilized in patients with refractory HE, but are not approved for clinical management.

Transfusing common sense instead of blood products into coagulation testing in patients with cirrhosis: Overtreatment ≠ safety

I n patients with cirrhosis the imbalance of procoagulants and anticoagulants combined with potential alterations in fibrinolysis and platelet number and function can alter standard laboratory coagulation testing. Prothrombin time and platelet count are frequently abnormal and, in our risk-averse health care system, often result in preprocedure transfusions to achieve “safer” thresholds. But what are we actually achieving: a risk of portal hypertensive bleeding, transfusion reaction, transfusion-related acute lung injury, infection transmission, human leukocyte antigen (HLA) antibody development, superior test results, or improved coagulation? According to the International Symposium on Coagulopathy and Liver Disease, rebalanced hemostasis is what we need to measure, which stems from both the prohemostatic and antihemostatic pathways working in concert. Disproportionately fewer nonportal hypertensionrelated bleeding complications occur in patients with cirrhosis relative to their prothrombin time and platelet values. This results from relatively rebalanced hemostasis. Despite this, many health care professionals continue to transfuse blood products (i.e., fresh frozen plasma [FFP] and platelets) prophylactically to improve laboratory profiles, regardless of function and prior data demonstrating a low risk of bleeding complications in patients with cirrhosis, especially for minimally invasive procedures like paracentesis. Fortunately, the study by De Pietri and colleagues in this issue of HEPATOLOGY offers an alternative to unnecessary preprocedural use of blood products in patients with cirrhosis with an elevated international normalized ratio (>1.8) and/or thrombocytopenia (<50 3 10/lL) using thromboelastography (TEG) to guide transfusions. TEG was adopted into clinical practice in 1985, more than 35 years after the procedure was first pioneered for research purposes. Using approximately 0.35 mL of whole blood in an oscillating cup at 37C, this test uses mechanically transduced waves at different rates to graphically illustrate the patient’s coagulation function. TEG is already used clinically in liver transplant, cardiovascular, trauma, and obstetric surgery where dynamic changes in blood volume and coagulation occur. This semiautomated bedside instrument easily yields an overall coagulation assessment in 30 minutes, with prolonged times resulting in blood product transfusions. A prolonged reaction time measures clot formation, indicative of coagulation factor function and results in transfusion (i.e., usually FFP), while a prolonged maximum amplitude measures clot strength, indicative of platelet function and results in transfusion. The authors of this open-label, intention-to-treat trial randomized patients to TEG-guided transfusion where patients only received transfusion if their functional coagulation was altered versus standard of care preprocedural prophylactic transfusion therapy. Of note, only 16.7% of TEG-guided patients received transfusions compared to 100% of patients in the standard of care arm (P 5 0.009). Although platelet levels >50,000/lL have sufficient thrombin production, the use of FFP and platelet transfusions in patients with cirrhosis rarely, if ever, achieves complete normalization of coagulation parameters by standard testing. Of note, although allogenic transfusions at times are necessary, their cost and more importantly risk must also be taken into account (Table 1). The risk of overtransfusion was highlighted in a recent randomized controlled trial comparing liberal (hemoglobin <9 g/dL) versus restrictive (hemoglobin <7 g/dL) pack red blood cell (RBC) transfusion strategies in acute upper gastrointestinal bleeding. This trial subsequently resulted in a lower hemoglobin threshold (<7 g/dL) for RBC transfusion in general clinical care. Furthermore, liberal blood transfusions in patients with cirrhosis, compared to restrictive strategies, had the Abbreviations: FFP, fresh frozen plasma; HLA, human leukocyte antigen; RBC, red blood cell; TEG, thromboelastography. Received September 29, 2015; accepted October 12, 2015. Address reprint requests to: Jacqueline G. O’Leary, M.D., M.P.H., Medical Director of Research, Baylor Simmons Transplant Institute, Baylor University Medical Center, 3410 Worth Street, Suite 860, Dallas, TX 75246. E-mail: JacquelO@BaylorHealth.edu; tel: 11-214-820-8500; fax: 11-214-820-0993. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28291 Potential conflict of interest: Dr. O’Leary received grants from Fisher Scientific.

Hepatic encephalopathy: how to test and treat.

Purpose of review Hepatic encephalopathy causes significant cognitive impairment and morbidity in patients with cirrhosis; however, hepatic encephalopathy is considered a reversible syndrome once recognized clinically. Although hepatic encephalopathy is not a single clinical entity, the pathophysiology resulting in brain dysfunction is not fully understood, although it is believed that ammonia production is an important contributing factor. The purpose of this review is to highlight studies used to test for hepatic encephalopathy and those utilizing specific new treatments. Recent findings A ‘STROOP’ smartphone app has been developed to allow clinicians to test for covert hepatic encephalopathy (CHE). Lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent overt hepatic encephalopathy (OHE) episodes. In patients without prior OHE, probiotics can be useful in preventing OHE. Lactulose, probiotics, L-ornithine-L-aspartate, and potassium-iron-phosphate-citrate have been studied in the treatment of CHE. Rifaximin was found to be safe and well tolerated in long-term maintenance of remission from OHE; however, compared to lactulose therapy in CHE, it is not cost-effective. Summary Refinement in clinical management strategies for patients with cirrhosis and hepatic encephalopathy appears to continue to contribute to improved patient outcomes.